Silver sulfadiazine was first described in 1943 by Wruble and was found to be mildly antiseptic. U.S. Pat. No. 3,761,590 describes a process for preparing a thick cream ointment containing silver sulfadiazine, which rejuvenated the compound for the topical treatment of burns. The 1% w/w of this active drug, in the form of a cream, has been in clinical use in the USA since 1973.
Chlorhexidine is a bisbiguanide antiseptic and disinfectant effective against a wide variety of bacteria, some fungi, and some viruses. It is used clinically in various preparations for disinfecting purposes.
The antimicrobial effect of silver sulfadiazine and chlorhexidine compounds has been clinically established. It has been well known that silver sulfadiazine is effective against a wide variety of gram-positive and gram-negative organisms, including Pseudomonas and Candida. 
The prior art discloses a number of formulations of silver sulfadiazine for treatment of burns.
European Publication No. 0 326 145 discloses a composition for the topical treatment of herpes infections, varicella, eczema, and burns (2nd and 3rd degree) comprising 0.01% w/w to 10% w/w silver sulfadiazine, 0.01% w/w to 10% w/w polyhydric alcohol, and optionally a local anesthetic.
Belgian Patent No. 892,421 relates to stable ointments and lotions containing silver sulfadiazine and a hydrophilic excipient for the treatment of mucosal infections without causing irritation.
French Patent No. 2,424,740 describes lotions, ointments, and powders containing finely divided silver sulfadiazine or zinc sulfadiazine. These salts were prepared in situ from sodium sulfadiazine. A lotion was prepared by dissolving sodium sulfadiazine in water, homogenizing with Tween® 80, paraffin, isopropyl palmitate, sorbitan monooleate, Myrj® 52, and stearyl alcohol. The mixture was homogenized with silver nitrate in water at 3000 rpm to form finely divided silver sulfadiazine with a particle size of <5 μm, and with 90% of particles <0.7 μm.
Indian Patent Application No. 1038/KOL/2005 relates to a therapeutic composition for treating burn injury and lesions, comprising the following active ingredients in the amounts given below (a) sucralfate—1% w/w to 8% w/w; (b) silver sulfadiazine—0.5% w/w to 2% w/w; and (c) chlorhexidine gluconate—0.1% w/w to 0.3% w/w, in admixture with pharmaceutically acceptable excipients, adjuvants, fillers, humectants and/or stabilizers. It also relates to a process for preparing the above-mentioned therapeutic composition for burn wound management.
U.S. Pat. No. 6,987,133 discloses a topical spray preparation for burn treatment comprising silver sulfadiazine dispersed or solubilized in the cream or lotion base matrix, which can be sprayed directly from a common trigger spray device.
Commercial formulations containing chlorhexidine gluconate 0.2% w/w, and silver sulfadiazine 1% w/w, e.g., Silvazine®, Nisburn®, or Silverex® cream, are available in the market; however, the particle size range of silver sulfadiazine in these formulations is in the micronized range.
The activity of silver sulfadiazine, in the cream form, may be influenced by the following factors:                (a) the release rate of the active ingredient from the cream matrix into the wound environment;        (b) particle size and solubility of the active ingredient in the fluids of the wound; and        (c) stability of the active ingredient in the cream matrix.        
Among these factors, particle size is one of the most critical parameters which affects the solubility and release of the active ingredient from the pharmaceutical composition at the wound site. Smaller particle size will lead to increased antimicrobial effectiveness. Therefore, further size reduction of silver sulfadiazine particles as compared to the marketed micronized product may result in greater antimicrobial effectiveness based on enhanced solubility of silver sulfadiazine. However, this size reduction may lead to stability concerns as well.
Particle size reduction to improve the drug performance has long been known and used in the pharmaceutical industry. Nanonization, i.e., particle size reduction to the nano-size range is a known technique for improving the solubility of the active ingredient, thereby leading to improved absorption and better therapeutic efficacy. However, the selection of the optimum particle size range as well as the selection of the method for particle size reduction remains critical for the chosen active drug. Further, achieving the desired stability throughout the shelf life is equally important.
Nesamony et al, in their article entitled “IPM/DOSS/Water Microemulsions as Reactors for Silver Sulfadiazine Nanocrystal Synthesis”, published in Journal of Pharmaceutical Sciences, Volume 94, No. 6, pp. 1330-1320 (2005), have disclosed a method of preparing silver sulfadiazine nanocrystals in situ by mixing sodium sulfadiazine and silver nitrate using a microemulsion technique. The silver sulfadiazine nanocrystals so prepared have a particle size of ˜670 nm, as measured by laser diffraction technique. Preparation of nanocrystals using microemulsion technique is a complex process.
There still remains a need for a topical pharmaceutical composition comprising nanonized silver sulfadiazine demonstrating improved efficacy over the already marketed product.
The object of the present invention is to provide a topical pharmaceutical composition comprising an antimicrobial drug, i.e., silver sulfadiazine in a weight ratio of 0.1% w/w to 1.0% w/w and an antiseptic, i.e., chlorhexidine gluconate in a weight ratio of 0.2% w/w, wherein silver sulfadiazine is in nano-size range. The pharmaceutical composition of the present invention is advantageous over the currently available micronized products in having improved efficacy, thereby leading to dose reduction as well as faster wound healing due to quicker absorption of nanonized particles having increased surface area. Also, no significant increase in toxicity was observed as a result of size reduction. The inventors were able to obtain a stable pharmaceutical composition of silver sulfadiazine having nanonized particles of silver sulfadiazine. The compositions of the invention comprising 0.5% w/w and 0.75% w/w nanonized silver sulfadiazine have comparable efficacy to the 1.0% w/w marketed product (micronized silver sulfadiazine) in patients with partial thickness thermal burns. Comparable efficacy provides significant dose reduction to a patient in need of silver sulfadiazine for burn treatment. The composition containing 1.0% w/w nanonized silver sulfadiazine shows greater efficacy than the 1.0% w/w marketed product (micronized silver sulfadiazine).